Controlled release compositions of gamma-hydroxybutyrate

ABSTRACT

The present invention is directed to oral pulse-release pharmaceutical dosage form containing an immediate release component of gamma-hydroxybutyric acid, and one or more delayed/controlled release components of gamma-hydroxybutyric acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/614,622, filed Sep. 30, 2004.

FIELD OF THE INVENTION

The present invention is directed to pulse-released formulations ofoxybate, or gamma-hydroxybutyric acid, salts, which reduce the number ofdosages typically required for treatment. For instance, in the treatmentof narcolepsy, a twice-nightly dosage regimen can be reduced to a singledose with the compositions of the present invention.

BACKGROUND OF THE INVENTION

Sodium gamma-hydroxybutyrate (GHB or sodium oxybate) is a naturallyoccurring metabolite of many mammalian tissues (Fishbein et al, J. BiolChem. 239:357-61 (1964), Mamelak, Neurosci Biobehav Rev. 13(4):187-98(1989), Nelson etal, J. Neurochem., 37:1345-48 (1981)) and has broadindications including narcolepsy, cataplexy, sleep paralysis,alcoholism, chronic schizophrenia, catatonic schizophrenia, atypicalpsychoses, chronic brain syndrome, neurosis, drug addiction andwithdrawal, Parkinson's disease and other neuropharmacologicalillnesses, hypertension, ischemia, circulatory collapse, radiationexposure, cancer, myocardial infarction, anesthesia induction, sedation,growth hormone production, heightened sexual desire, anorectic effects,euphoria, smooth muscle relaxation, muscle mass production, and sleep.

Currently, sodium gamma-hydroxybutyrate is prescribed for patients withnarcolepsy (Xyrem®, Orphan Medical) as a twice-nightly solution.Patients take an initial dose of sodium gamma-hydroxybutyrate aroundbedtime and must wake up four hours later to take a second dose. Such adose regimen is rather inconvenient.

Other dosage forms of sodium gamma-hydroxybutyrate have also beendisclosed. For example, U.S. Pat. No. 5,594,030 discloses controlledrelease pharmaceutical compositions of gamma hydroxybutyric acid saltsconsisting of a nucleus in the form of granulates or tablets whichcomprises GHB and a cellulosic matrix, wherein the drug substance isreleased within 7 to 8 hours.

Sodium gamma-hydroxybutyrate is highly soluble, hygroscopic, andstrongly alkaline, and the therapeutic dose is normally very high. Forexample, a daily dose of 4.5 to 9 grams of Xyrem® is prescribed tonarcolepsy patients. These characteristics of sodiumgamma-hydroxybutyrate have some significant effects on coated particlesor tablets comprising GHB. The high solubility of sodiumgamma-hydroxybutyrate likely leads to drug migration into the coatinglayer during the coating process, and dissolves rapidly when the coatedarticles encounter water or bodily fluids, creating “pores” that allowleakage of the drug from the coated articles. Further, when sodiumgamma-hydroxybutyrate penetrates/diffuses into the coating film, it mayinterfere with the coating material itself. For example,penetrated/diffused sodium gamma-hydroxybutyrate may act as a strongbase which reacts with pH sensitive coating polymers, such as EudragitL30-D55 for instance, weakening the coating layer and lowering thecoating efficiency.

Further, the absorption of sodium gamma-hydroxybutyrate seems to becapacity-limited (Palatini et al, Eur. J Clin Pharmacol. (1993)45:353-356), but it has been unclear whether the absorption of this drugis region-specific, which would affect the oral delivery of GHB.

Therefore, a need exists in the art for a more convenient dosingregimen, an effective dosage form of controlled release ofgamma-hydroxybutyric acid salts and an efficient way to delivergamma-hydroxybutyric acid salts to an animal in the gastrointestinaltract. The current invention satisfies these needs.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a convenient andeffective dosage form of GHB, whereby the number of dosages can bereduced.

It is another object of the present invention to provide compositions ofGHB that have a reduced likelihood of drug migration from the dosageform.

The present invention takes into account the surprising discovery by thepresent inventors that the oral absorption of sodiumgamma-hydroxybutyrate is region specific in animals, and that theabsorption is higher in the upper GI tract than in the lower GI tract.

The present invention is also directed to methods and compositions forthe targeting of the upper GI tract of an animal for improved absorptionof sodium gamma-hydroxybutyrate.

The current invention provides methods and compositions for convenientadministration of multiple doses of one or more gamma-hydroxybutyricacid salts to an animal. It provides a convenient once nightly or oncedaily dose regiment for the oral delivery of one or moregamma-hydroxybutyric acid salts to an animal. With the compositions ofthe present invention, a patient does not need to wake up at night totake a second dose then go back to sleep.

The current invention also provides methods and compositions for theeffective delayed/controlled release of multiple (i.e., more than one)doses of one or more gamma-hydroxybutyric acid salts. The currentinvention provides methods and compositions to improve thegastro-stability of delayed/controlled release particulates (e.g. beads,granules, minitabs or pellets) containing gamma-hydroxybutyric acidsalts.

The current invention further provides methods and compositions for theeffective delivery of multiple doses of gamma-hydroxybutyric acid saltsto one or more specific regions in the gastrointestinal tract of ananimal. It provides methods and compositions for the targeting of theupper GI tract of an animal to improve the effectiveness of theabsorption of gamma-hydroxybutyric acid salts from thedelayed/controlled release particles.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Dissolution profile of a colon-targeting delayed releaseprototype with a neutralizing agent in the barrier coat.

FIG. 2. Dissolution profile of a colon-targeting delayed releaseprototype without a neutralizing agent in the barrier coat.

FIG. 3. Dissolution profile of a duodenum-targeting delayed releaseprototype without a neutralizing agent in the barrier coat.

FIG. 4. Dissolution profile of an immediate release core of the presentinvention.

FIG. 5. Dissolution profile of an Opadry AMB-coated immediate releasecore of the present invention.

FIG. 6. Dissolution profile of an ethylcellulose-coated immediaterelease core of the present invention.

FIG. 7. Dog pharmacokinetic profiles—demonstrating region of absorption.

DETAILED DESCRIPTION OF THE INVENTION

The current invention provides methods and compositions for convenientadministration of multiple (i.e. more than one, “pulsed”) doses of oneor more gamma-hydroxybutyric acid salts to an animal.

It also provides methods and compositions for the effectivedelayed/controlled release of multiple doses of one or moregamma-hydroxybutyric acid salts.

The current invention provides methods and compositions to improve thegastro-stability of the delayed/controlled release particles containinggamma-hydroxybutyric acid salts.

The current invention further provides methods and compositions for theeffective delivery of multiple doses of gamma-hydroxybutyric acid saltsto one or more specific regions in the gastrointestinal tract of ananimal for effective absorption.

Specifically, at the essence of the present invention is a dosage formcomprising one or more pH sensitive delayed/controlled release particles(e.g. beads, granules, minitabs or pellets), wherein each of the pHsensitive delayed/controlled release particles is composed of animmediate release core comprising one or more gamma-hydroxybutyric acidsalts and one or more pharmaceutically acceptable excipients, one ormore barrier coats surrounding such core (with or without a neutralizingagent), a pH sensitive enteric release coat around said barrier coat,and optionally an overcoat.

The dosage forms of the current invention comprise an immediate releasecomponent in the form of a solid, a semi-solid or a liquid, comprisingone or more gamma-hydroxybutyric acid salts and optionally one or morepharmaceutically acceptable excipients, wherein the immediate releasecomponent is present together with (or separated contained from) one ormore pH sensitive delayed/controlled release particles.

The dosage forms thus provide, which administered together orsequentially, multiple release pulses of gamma-hydroxybutyric acid saltstargeting multiple regions in the gastrointestinal tract of an animalfor improved absorption.

In one of the preferred embodiments, the composition comprises multipledelayed release pellets or beads (used interchangeably herein) and animmediate release component. In a most preferred embodiment, the dosageform comprises a liquid immediate release component, and twodelayed/controlled release pellets/beads.

Each of the pH sensitive delayed/controlled release particles in thecurrent invention is designed to release its contents at a specificregion in the gastrointestinal tract of an animal. The one or more pHsensitive delayed/controlled release particles releases the contents atone or more corresponding regions in the gastrointestinal tract of ananimal.

The immediate release component, in the form of a solid, a semi-solid ora liquid, of the current invention releases its contents immediately forabsorption upon oral administration. Preferably, due to the high dosageof GHB, the immediate release component is a liquid.

Combining the immediate release component and one or more pH sensitivedelayed/controlled release particles of the current invention canconstitute a complete once-nightly or once-daily dose. The term“combining” as used herein means supplying and consuming all components(1) simultaneously in the same presentation or dosage form, or (2)simultaneously in different presentations or dosage forms, or (3)sequentially in the same presentation or dosage forms, or (4)sequentially in different presentations or dosage forms.

For example, an immediate release component in the form of particles andone or more pH sensitive delayed/controlled release particles aresupplied as pre-mixed doses, and are consumed simultaneously at the timeof dosing. Or, an immediate release component in the form of particlesand one or more pH sensitive delayed/controlled release particles aresupplied in separated parts, and are consumed simultaneously at the timeof dosing. Alternatively, an immediate release component in the form ofa powder and one or more pH sensitive delayed/controlled releaseparticles are supplied in separate parts, and are consumedsimultaneously at the time of dosing. In another embodiment, animmediate release component in the form of a solution and one or more pHsensitive delayed/controlled release particles are supplied in separateparts, and are consumed simultaneously at the time of dosing. Or, animmediate release component in the form of a solution and one or more pHsensitive delayed/controlled release particles are supplied in separatedparts, and are consumed sequentially at the time of dosing. Otherpermutations would be apparent in those skilled in the art.

In one embodiment of the present invention, the delayed/controlledrelease component(s) is/are administered prior to the immediate releasecomponent, which can be administered from several minutes to about ahalf hour or more later (for practical reason, likely no more than aboutan hour later because the patient will become somewhat sleepy from thefirst dose). Thus, in it's most basic form, the present invention isdirected to the delayed/controlled release component(s), which haveutility as a separately administrable dosage form. These components canbe supplied as a separate entity, and preferable used in conjunctionwith an immediate release dosage form as is currently marketed.

Multiple (i.e. more than one) delayed releases can be achieved bycombining multiple pH sensitive delayed/controlled release particlestargeting certain sites of the GI tract of an animal. For example, animmediate release component can be combined with two pH sensitivedelayed/controlled release particles that are released at two differentsites in the GI tract to provide an immediate release and two otherdelayed release pulses.

An immediate release component can be combined with one type of pHsensitive delayed/controlled release particles to provide two pulses ofgamma-hydroxybutyric acid salts, which can conveniently replace thenightly multi-dose regimen of the existing commercial product. In thiscase, a patient does not need to wake up and take a second dose duringthe night, as described earlier.

Preferably, an immediate release component is combined with one or morepH sensitive delayed/controlled release particles to provide multiplereleases in a period of time. Preferably, an immediate release componentis combined with one or more pH sensitive delayed/controlled releaseparticles targeted to the upper GI tract of an animal. The inventorsdiscovered that the absorption of sodium gamma-hydroxybutyrate in the GItract of an animal is site specific, and that the absorption of sodiumgamma-hydroxybutyrate in the upper GI tract is higher than in the lowerGI tract. The aforementioned combination therefore provides an initialdose and one or more delayed doses of gamma-hydroxybutyric acid salts,thereby providing an effective and convenient dose regimen for treatinga patient.

More preferably, an immediate release component is combined with asingle type of pH sensitive delayed/controlled release particlestargeted to the duodenum or the jejunum of an animal to provide atwo-pulse regiment to treat a patient.

The dose ratio of the immediate release component to one or more pHsensitive delayed/controlled release particles is dictated by the typeof therapy and readily determined by the clinician, using currentlyavailable dosages as a reference. For example, the immediate releasedose can be equivalent of, higher than, or lower than, the one or moredelayed release doses.

It is contemplated that the delayed release dose amount, which is usedto replace the second nightly dose (currently as a solution) in thecurrent treatment of narcolepsy patients, can be the same as theimmediate release dose amount, although the bioavailability is lowerfurther along the GI tract, or even at a reduced dose amount, since thepatients do not need to wake up and take a separate second nightly dosethen go back to sleep.

It is also contemplated that the immediate release component can be at aslightly higher than normal dose, and the delayed release dose can be ata normal dose or at a reduced dose.

It is also contemplated that an immediate release component can becombined with one or more pH sensitive delayed/controlled releaseparticles that are at reduced doses. For example, an immediate releasedose can be combined with 0.7 equivalent dose of a duodenum-targetingdelayed release component and 0.2 equivalent dose of a colon-targetingdelayed release component to give a broader time coverage.

The immediate release component and one or more pH sensitivedelayed/controlled release particles of the current invention can beadministered to an animal directly, or mixed/sprinkled with fluids, softfoods (i.e. yogurt, applesauce), or pharmaceutically acceptablecarriers. For example, an immediate release component in the form of asolution can be mixed with juice and the pH sensitive delayed/controlledrelease particles can be combined with foods (such as yogurts) foradministration. Or, an immediate release component in the form ofparticles and the pH sensitive delayed/controlled release particles canbe sprinkled with drinkable yogurt for dosing.

The Immediate Release Component

The dosage forms of the current invention comprise an immediate releasecomponent in the form of a solid, a semi-solid or a liquid. It can be aparticle, a bead, a pellet, a granulate, a powder, a tablet, aminitablet, a capsule, a caplet, a lozenge, a hard shell or soft shellcapsule, a sachet, a cachet, a solid dispersion, a solid solution, asuspension, an emulsion, a lotion, a solution, a liquid drop, an elixir,a syrup, a tincture, a liquid spray, an aerosol, a gel, an ointment, acream, or the like.

The immediate release component can be present together with one or moreof the pH sensitive delayed/controlled release particles describedherein, or separated from the pH sensitive delayed/controlled releaseparticles.

For example, the immediate release component can be in the form ofparticles that are pre-mixed with the pH sensitive delayed/controlledrelease particles. Or the two components can be provided as separateparts, possibly in a kit, wherein both components can be consumedtogether, or separately in a sequential manner.

In another example, the immediate release component can be in the formof a powder that is pre-mixed with the pH sensitive delayed/controlledrelease particles prior to ingestion. In this embodiment, the immediaterelease component is a powder comprising up to 100% of one or moregamma-hydroxybutyric acid salts and optionally one or morepharmaceutically acceptable excipients. Such a powder can be taken asis, or preferably is stirred into a drink or food along with thedelayed/controlled release beads/pellets/minitabs.

In another preferred embodiment, the immediate release component is anaqueous solution (like the current Xyrem® product) of one or moregamma-hydroxybutyric acid salts stabilized with antioxidants,stabilizers, preservatives and neutralizing agents.

In yet another example, which is preferred because of the very highdosage needed for this drug, the immediate release component can be inthe form of a solution that is provided separately from the pH sensitivedelayed/controlled release particles, possibly in a kit form. Theimmediate release component is an aqueous solution (like the currentXyrem®) product) of one or more gamma-hydroxybutyric acid saltsstabilized with antioxidants, stabilizers, preservatives andneutralizing agents. Preferably, the delayed release particles are mixedwith the liquid and then ingested.

The immediate release component of the current invention comprises oneor more gamma-hydroxybutyric acid salts and optionally one or morepharmaceutically acceptable excipients, wherein the gamma-hydroxybutyricacid salts are selected from gamma-hydroxybutyric acid sodium salt,gamma-hydroxybutyric acid potassium salt, gamma-hydroxybutyric acidtetraammonium salt, or any other pharmaceutically acceptable salt formsof gamma-hydroxybutyric acid.

The immediate release component comprises from about 20% to about 100%by weight of one or more gamma-hydroxybutyric acid salts and optionallyone or more pharmaceutically acceptable excipients.

The pharmaceutically acceptable excipients in the immediate releasecomponent are those known in the art as suitable for use in solid,semi-solid or liquid dosage forms, including but not limited to,binders, lubricants, anti-adherents, glidants, granulating aids,fillers, disintegrants, antioxidants, stabilizers, preservatives,neutralizing agents, buffering agents, tonicifiers, moisture absorbents,colorants, flavorants, sweeteners, sugars, and taste-masking agents,suspending agents, thickening agents, gelling agents, solvents,solubilizers, surfactants, absorption enhancers, emulsifying agents, andcombinations thereof.

The total amount of these pharmaceutically acceptable excipients in theimmediate release component is from about 0% to about 80% by weight.

Examples of these pharmaceutically acceptable excipients in theimmediate release component of the current invention include, but arenot limited to, binders/fillers: microcrystalline cellulose, silicifiedmicrocrystalline cellulose, polyvinylpyrrolidone, hydroxypropylcellulose, starch, pregelatinized starch, starch paste, lactose,mannitol, sorbitol, xylitol, sucrose, calcium phosphate, calciumcarbonate, ethylcellulose, methylcellulose, and Acacia;lubricants/anti-adherents/glidants/granulating aids: talc, sodium laurylfumarate, fumed silicon dioxide, colloidal silica, titanium dioxide,kaolin, magnesium stearate, calcium stearate, stearic acid, hydrogenatedvegetable oils, and sodium lauryl sulfate; disintegrants: sodium starchglycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, andalginic acid; antioxidants/stabilizers/preservatives: riboflavin,tocopherol, vitamin E TPGS, BHT, BHA, cysteine and derivatives,ascorbates, sorbates, benzoates, propionates, bicarbonates,thiosulfates, metabisulfites, EDTA, carrageen, gums and benzyl alcohol;neutralizing agents: acids such as malic acid, citric acid, tartaricacid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoicacid, polyacids, acidic ionic resins, and other acidic excipients;suspending agents/thickening agents/gelling agents: mineral oils,vegetable oils, silicon dioxide, various gums such as xanthan gum,locust bean gum, gum Arabic, alginates, Carbopols, polyvinyl alcohols,carrageenan, gelatin, starches; or mixtures thereof.

Preferably, if the immediate release component is a solid pellet, beador minitablet or the like, that component is also used as the immediaterelease core of the pH sensitive delayed/controlled release particles bycoating them using materials and methods similar to the barrier coats orthe overcoat as described herein.

Delayed/Controlled Release Particles

The immediate release core of the pH sensitive delayed/controlledrelease particles (i.e., beads, pellets, minitabs, granulate, etc.) ofthe current invention comprises from about 20% to about 99% of one ormore gamma-hydroxybutyric acid salts by weight of the core and one ormore pharmaceutically acceptable excipients, wherein thegamma-hydroxybutyric acid salts are selected from gamma-hydroxybutyricacid sodium salt, gamma-hydroxybutyric acid potassium salt,gamma-hydroxybutyric acid tetraammonium salt, or any otherpharmaceutically acceptable salt forms of gamma-hydroxybutyric acid, orcombinations thereof.

One or more pharmaceutically acceptable excipients in the immediaterelease core of the pH sensitive delayed/controlled release particles ofthe current invention are excipients known in the art as suitable foruse in particulates, including but not limited to binders, lubricants,anti-adherents, glidants, granulating aids, fillers, disintegrants,antioxidants, stabilizers, preservatives, neutralizing agents, bufferingagents, moisture absorbents, colorants, flavorants and task-maskingagents.

The total amount of these pharmaceutically acceptable excipients in theimmediate release core is from about 1% to about 80% by weight of thecore.

Examples of these pharmaceutically acceptable excipients in theimmediate release core of the current invention include, but are notlimited to, binders/fillers: microcrystalline cellulose, silicifiedmicrocrystalline cellulose, polyvinylpyrrolidone, hydroxypropylcellulose, starch, pregelatinized starch, starch paste, lactose,mannitol, sorbitol, xylitol, sucrose, calcium phosphate, calciumcarbonate, ethycellulose, methylcellulose, and Acacia;lubricants/anti-adherents/glidants/granulating aids: talc, sodium laurylfumarate, fumed silicon dioxide, colloidal silica, titanium dioxide,kaolin, magnesium stearate, calcium stearate, stearic acid, hydrogenatedvegetable oils, and sodium lauryl sulfate; disintegrants: sodium starchglycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, andalginic acid; antioxidants/stabilizers/preservatives: riboflavin,tocopherol, vitamin E TPGS, BHT, BHA, cysteine and derivatives,ascorbates, sorbates, benzoates, propionates, bicarbonates,thiosulfates, metabisulfites, EDTA, carrageen, gums and benzyl alcohol;neutralizing agents: acids such as malic acid, citric acid, tartaricacid, ascorbic acid, oleic acid, capric acid, caprylic acid, benzoicacid, polyacids, acidic ionic resins, and other acidic excipients; ormixtures thereof.

Preferably, the immediate release core of the current inventioncomprises one or more excipients selected from binders, lubricants,anti-adherents, glidants and neutralizing agents.

The lubricants/anti-adherents/glidants may be selected from talc, sodiumlauryl fumarate, fumed silicon dioxide, magnesium stearate and stearicacid, for instance. Preferably, the lubricants/anti-adherents/glidantsare selected from one or both of talc and magnesium stearate.

In a preferred embodiment, the amount of talc in the immediate releasecore of the current invention about 1% to about 25% by weight of thecore. More preferably, this amount is from about 5% to about 15% byweight of the core.

If magnesium stearate is used in the core it is present in an amount offrom about 0% to about 10% by weight of the core. More preferably, thisamount is from about 0.1% to about 5% by weight of the core.

Preferably, the binders/fillers in the immediate release core areselected from microcrystalline cellulose, silicified microcrystallinecellulose, polyvinylpyrrolidone, and hydroxypropyl cellulose.

Preferably, the immediate release core comprises microcrystallinecellulose or silicified microcrystalline cellulose at about 1% to about80%% by weight of the core. More preferably, the immediate release corecomprises microcrystalline cellulose or silicified microcrystallinecellulose at about 3% to about 40% by weight of the core.

Preferably, the immediate release core comprises a neutralizing agent.The uptake of gamma-hydroxybutyric acid salts may be affected by theenvironmental pH and the ionization state of the salts. Preferably, theimmediate release core contains a neutralizing agent to modulate theionization state of the salt for better absorption in thegastrointestinal tract.

The immediate release cores in the pH sensitive delayed/controlledrelease particles of the current invention are made by techniques andequipment known in the art, for example dry blending, milling, drygranulation, wet granulation, pelletization, direct pelletization,extrusion, melt-extrusion, spheronization, drug layering, compaction,compression. Solvents can be used to facilitate the preparation of theimmediate release core. These solvents can be removed partially orcompletely during the preparation of the core. Suitable solventsinclude, but are not limited to, water, alcohols, ketones andcombinations thereof. For example, water and/or alcohols can be usedduring wet granulation and spheronization, or during directpelletization, or during drug layering, and the solvents can be removedthereafter.

Barrier Coat(s)

One or more barrier coats applied to the pH sensitive delayed/controlledrelease particles of the current invention provides a barrier, and aneutralization zone when a neutralizing agent is used, between theimmediate release core and the enteric coat, and functions to preventgamma-hydroxybutyric acid salts from entering into or interfering withthe enteric coat. The barrier coats can optionally act also as acontrolled release coat to control the rate of release ofgamma-hydroxybutyric acid salts from the immediate release core.

The barrier coats in the current invention provide a barrier andoptionally a neutralization zone between the immediate release core andthe enteric coat to prevent the alkalinic gamma-hydroxybutyric acidsalts from migrating into and interfering with the pH sensitive entericcoat. If the highly water-soluble and strongly alkalinicgamma-hydroxybutyric acid salts migrate into the enteric coat, they notonly create channels in the enteric coat which act as pore formers, butalso react with the functional groups of the coat materials and weakenthe enteric coat. By controlling the thickness and/or the permeabilityof the barrier coats, the migration of gamma-hydroxybutyric acid saltscan be minimized. Further, neutralizing agents, mainly acidifiers, canbe used in the barrier coat to neutralize gamma-hydroxybutyric acidsalts in the barrier layer thus preventing these alkalinic salts fromreacting with the enteric coat material.

Moreover, the barrier coats can optionally act as a controlled releasecoat to control the rate of release of gamma-hydroxybutyric acid saltsfrom the immediate release core, allowing for site specific andcontrolled release of gamma-hydroxybutyric acid salts in the GI tract ofan animal.

Suitable coating materials for the barrier coats in the currentinvention include, but are not limited to, cellulosic polymers such asethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate,polyvinyl alcohol, or other water-based or solvent-based coatingmaterials.

Suitable neutralizing agents in the barrier coats of the currentinvention include, but are not limited to, acids such as malic acid,citric acid, tartaric acid, ascorbic acid, oleic acid, capric acid,caprylic acid, benzoic acid, polyacids (a polymer with multiplecarboxylic acid functional groups or side chains, e.g. polymethacylicacid, or molecules with multiple acid functional groups, e.g. EDTA,ethylenediaminetetraacetic acid), acidic ionic resins, and other acidicexcipients, and are used in amounts sufficient to neutralize anymigrating gamma-hydroxybutyric acid salts. Preferably, the amount ofneutralizing agent in the barrier coat is at about 0.01% to about 10%mol/mol of the gamma-hydroxybutyric acid salts in the core. Morepreferably, this amount is at about 1% to about 5% mol/mol of the salts.

The barrier coats in the current invention can further comprise otheradditives known in the art, such as pore formers, plasticizers,anti-adherents, glidants, and antifoam agents. Pore formers suitable foruse in the barrier coats of the invention are organic or inorganicagents, and include materials that can be dissolved, extracted orleached from the coating in the environment of use. Examples of the poreformers include, but are not limited to, organic compounds such assaccharides including sucrose, glucose, fructose, mannitol, mannose,galactose, sorbitol, pullulan, dextran; polymers soluble in theenvironment of use such as water-soluble hydrophilic polymers,hydroxyalkylcelluloses, carboxyalkylcelluloses,hydroxypropylmethylcellulose, cellulose ethers, acrylic resins,polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethyleneoxide, Carbowaxes, Carbopol, and the like, diols, polyols, polyhydricalcohols, polyalkylene glycols, polyethylene glycols, polypropyleneglycols, or block polymers thereof, polyglycols, poly(a-w)alkylenediols;inorganic compounds such as alkali metal salts, lithium carbonate,sodium chloride, sodium bromide, potassium chloride, potassium sulfate,potassium phosphate, sodium acetate, sodium citrate, suitable calciumsalts, and the like. The amount of pore formers used in the barriercoats varies depending on the functions of the barrier coats. Forexample, if the pH sensitive delayed/controlled release particles areintended for immediate release after entering the targeted site in theGI tract, high amounts of pore formers (e.g. as high as about 50% byweight of the barrier coat) can be used. If the pH sensitivedelayed/controlled release particles are for controlled release afterentering the targeted site in the GI tract, little or no pore formersare used (e.g. no more than about 25% by weight of the barrier coat).

The rate of release of gamma-hydroxybutyric acid salts in the pHsensitive delayed/controlled release particles can also be controlled byvarying the thickness and/or types of the barrier coats, with or withoutthe use of pore formers. For example, when ethylcellulose is usedtogether with PVP K30 (5%) as the pore former, or when ethylcellulose isused with or without a water-insoluble plasticizer and without the useof any pore formers, or when ethylcellulose is used with a water-solubleplasticizer such as triethyl citrate, the barrier coat can be betweenabout % to about 20% weight gain on the particles in order to obtaindifferent controlled release profiles. Or, when Opadry AMB is used asthe barrier coat, the barrier coat can be from about 2% to about 10%weight gain on the particles, in order to obtain an immediate releaseprofile.

The barrier coats can also be multiple coats of different coatingmaterials. For example, the barrier coats can have an Opadry AMB initialbarrier coat, and an ethylcellulose secondary barrier coat surroundingthe initial coat, and optionally an Opadry tertiary barrier coatsurrounding the secondary coat.

The barrier coats can be water-based coatings, or organic solvent-basedcoatings. Preferably, the barrier coat is organic solvent-based coatingsuch as an alcohol or alcohol-water or ketone based coating.

Furthermore, the barrier coats of the current invention can providemoisture protection for hygroscopic gamma-hydroxybutyric acid saltsinside the barrier coats.

The pH Sensitive Enteric Coat

The pH sensitive enteric release coat of the current invention enablestargeted delivery of the particles to a specific region in the GI tract.It also provides a time delay in the release of the gamma-hydroxybutyricacid salts from the pH sensitive delayed/controlled release particles ofthe current invention. Combinations of more than one of these pHsensitive delayed/controlled release particles in a dosage form willprovide multiple doses of gamma-hydroxybutyric acid salts delivered tomultiple sites in the GI tract with multiple delay time periods orpulses. When combined with any controlled release characteristics of thebarrier coats, the compositions of the current invention provide a widespectrum of combined site specific, delayed and controlled releaseprofiles for oral delivery of gamma-hydroxybutyric acid salts to ananimal.

Materials suitable for use in the pH sensitive enteric coat of thecurrent invention are pH sensitive coating materials known in the art.The pH sensitive coating materials include, but are not limited to,methacrylate-based coating materials such as polymers of methacrylicacid and methacrylates (e.g. Eudragit L 100-55, Eudragit L 30-D55,Eudragit L 100, Eudragit S 100, Eudragit FS 30 D), cellulose-basedcoating materials such as cellulose acetate phthalate, carboxymethylethylcellulose, cellulose acetate trimellitate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, Shellac-based coating materials such as Emcoat 120Nand Marcoat 125, and other enteric coating polymers such as polyvinylacetate phthalate.

Other additives such as solvents, plasticizers (e.g. PEG, triethylcitrate, dibutyl secbate), anti-tack agents (e.g. talc), anti-foamagents, colorants, fillers/extenders, flavorants, surfactants (e.g.sodium lauryl sulfate), bases, buffers, and other suitable additivesknown in the art can also be used together with the pH sensitive entericcoating materials.

The coating can be organic solvent-based, or aqueous-based, or organicsolvent/aqueous based.

Preferably, the pH sensitive delayed/controlled release particles areprepared by coating the barrier-coated immediate release core with anappropriate pH sensitive coating material targeting to a specific regionin the GI tract of an animal. The weight gain of the pH sensitiveenteric coating is from about 10% to about 70% of the finalenteric-coated particle weight. Preferably, the weight gain of thiscoating is from about 20% to about 60% of the final enteric-coatedparticles. More preferably, the weight gain of this coating is about 30%to about 50% of the final enteric-coated particle weight.

The pH sensitive enteric release coat can target both the upper part andthe lower part of the GI tract of an animal. The pH sensitive entericcoat releases/dissolves in one of the stomach, the duodenum, thejejunum, the ileum, or the colon of an animal. Suitable pH sensitiveenteric coating materials targeting each of these regions in humans areknown in the art, such as Eudragit E 100 or Eudragit E PO (stomach),Eudragit L 30 D-55 and Eudragit L 100-55 (duodenum), Eudragit L 12.5 andEudragit L 100 (jejunum), Eudragit S 100 (ileum), and Eudragit FS 30 D(colon).

Preferably, the pH sensitive enteric release coat releases/dissolves inthe upper GI tract of an animal, which will allow for better absorptionof the drug. In a more preferred embodiment, the pH sensitive entericcoat releases/dissolves in the duodenum or the jejunum of an animal.

Optionally, acidifiers or bases can be added to the pH enteric coatingmaterials to adjust the target release/dissolution pH or region in theGI tract of an animal. Further, acidifiers in the pH sensitive entericcoat can also counteract the alkaline effect from any migratinggamma-hydroxybutyric acid salts. Suitable acidifiers are organic acidsor inorganic acids, acidic excipients, and the aforementionedneutralizing agents.

The delay in release of gamma-hydroxybutyric acid salts from theparticles of the current invention can be achieved by selectingdifferent pH sensitive enteric release coats targeting the desiredregions of the GI tract of an animal. Combinations of various particleswith different pH sensitive enteric coats thus provide multiple pulsesof gamma-hydroxybutyric acid salts with various delayed release times.

Overcoats

Optionally, the immediate and/or delayed/controlled release solid dosageforms of the current invention can be coated with an overcoat. Theovercoat can be a moisture barrier coat, a protection coat, a seal coat,a taste-masking coat, a flavor coat, a polish coat, a color coat, or anyother cosmetic coats. Suitable coating materials for such an overcoatare known in the art, including, but are not limited to, cellulosicpolymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose,microcrystalline cellulose carrageenan, and ethylcellulose.

Other additives known in the art can also be used in the overcoat, suchas solvents, plasticizers (e.g. PEG, triethyl citrate, dibutyl secbate),anti-tack agents (e.g. Talc), anti-foam agents, colorants,fillers/extenders, flavorants, and surfactants (e.g sodium laurylsulfate).

The invention now will be described with respect to the followingexamples; however, the scope of the present invention is not intended tobe limited thereby.

EXAMPLES Example 1 Compositions of the Immediate Release Core and/or theImmediate Release Component

TABLE 1 PD0231- PD0231- PD0231- PD0231- PD0231- PD0231- PD0231- PD0231-PD0231- PD0231- Ingredients 25 24A 24B 24C 19 17A 16 15A 12 10A Sodiumgamma- 80 80 84 80  80 80 80 90 40 80 hydroxybutyrate Avicel PH101 10 1510 10  20 10 15 10 58 — Talc  9  5  5 9 — — — — — — Magnesium  1 —  1 1— — — — — — stearate SMCC 50 — — — — — — — — — 15 Emcompress — — — — —10  5 — — — HPMC E5 — — — — — — — —  2 — PVP K30 — — — — — — — — —  5Lactose — — — — — — — — — — Water  10*   11.3*   11.3*   5.5*   11.3* 15*  15*  12*   10.5*  9* Ethanol — — — — — — — — —  9*

TABLE 2 PD0231- PD0231- PD0231- PD0231- Ingredients 10B 10C 9B 8A Sodiumgamma- 70 65 80 83 hydroxybutyrate Avicel PH101 — — — — Talc — — — —Magnesium — — — — stearate SMCC 50 28 35 17 17 Emcompress — — — — HPMCE5  2 — 1 — PVP K30 — — — — Lactose — — 2 — Water  20*  18* 10.8 9.5Ethanol — — — — Number in parts by weight. *Removed partially orcompletely during preparation

Example 2 Preparation of the Immediate Release Core

The immediate release core can be made by techniques or processes orequipments known in the art, including but are not limited to dryblending, milling, dry granulation, wet granulation, pelletization,direct pelletization, extrusion, melt-extrusion, spheronization, druglayering, as exemplified by the following preparations:

Dry powders of sodium gamma-hydroxybutyric acid, Avicel PH101, Talc andmagnesium stearate were screened and mixed briefly, then charged into ahigh shear granulator. Water was added to the mixture during thegranulation. The granulates were extruded through a screen with adesirable pore size then spheronized to yield pellets. The pellets weredried in an oven for a sufficient time, for example overnight, thenscreened.

Example 3 Moisture Protection Coat of the Immediate Release Core

Opadry AMB Coating Solution:

Opadry AMB  25 g Deionized water 475 g

Uncoated pellets from Example 2 (600 g) were charged into a fluid bedcoater. The Opadry AMB coating solution was sprayed onto the pelletswith a product temperature at 39° C. until 3% weight gain was reached toyield an Opadry AMB-coated immediate release core.

Example 4 Barrier Coats of the Immediate Release Core

Ethylcellulose Coating Solution:

Ethylcellulose 73.9 g PVP K90 1.72 g Triethyl citrate 8.1 g Isopropylalcohol 1000 g Ethyl alcohol 1000 g

Uncoated pellets from Example 2 (600 g) were charged into a fluid bedcoater. The ethylcellulose coating solution was sprayed onto the pelletswith a product temperature at 35° C. until 3%, 6% or 9.2% weight gainwas reached to yield the EC-coated immediate release core.

For a slower release core, PVP K90 is used at lower levels or can beomitted.

Example 5 Neutralizing Agent-containing Barrier Coats of the ImmediateRelease Core

Neutralizing Agent-containing Barrier Coat Solution:

Opadry White 30 g Malic acid 30 g Deionized water 540 g 

The 3% Opadry AMB-coated pellets (Example 3) were further coated withthe neutralizing agent-containing barrier coat solution to 10% weightgain. An additional coat of Opadry AMB was also applied to some of theresultant pellets.

Example 6 pH Sensitive Enteric Release Coatings

Enteric Coating Solution 1 (Duodenum):

Eudragit L 30 D-55 840 g Triethyl citrate  12 g Talc  24 g Deionizedwater 324 g

Enteric Coating Solution 2 (Jejunum):

Eudragit L 100 390 g Talc  24 g Triethyl citrate  34 g Isopropyl alcohol2460 g  Acetone 377 g Deionized water 390 g

Enteric Coating Solution 3 (Colon):

Eudragit FS 30 D 540 g Triethyl citrate  9 g Talc  45 g Deionized water304 g

(a) The ethylcellulose (EC)-coated immediate release core from Example 4was further coated with enteric coating solution (1) to 40%, 45% or 50%weight gains to yield the duodenum-targeting particles.

(b) The EC-coated immediate release core from Example 4 was furthercoated with enteric coating solution (2) to 40%, 45%, 50%, or 60% weightgain to yield the jejunum-targeting particles.

(c) The Opadry AMB coated immediate release core from Example 3 wasfurther coated with enteric coating solution (3) to 40%, 45% or 50%weight gain to yield the colon-targeting particles.

(d) The core coated with neutralizing agent-containing barrier coatsfrom Example 5 was coated with an additional coat with enteric coatingsolution (3) to 40%, 45% or 50% weight gain to yield the colon-targetingparticles.

Example 7 Dissolution Profiles of Various Prototypes—Gastro-stabilityImprovement by the Neutralizing Agent in the Barrier Coats

Delayed/Controlled Release Prototypes

Colon-targeting prototype having a neutralizing agent (malic acid) inthe barrier coat (PD0231-26B-50) does not release any sodiumgamma-hydroxybutyrate at pH 1.1 and pH 6.0 for up to 3 hours (FIG. 1),whereas the one without the neutralizing agent in the barrier coat(PD0231-31 F-50) releases 3% at pH 1.1 in 2 hours and 12% at pH 6.0 in 1hour (FIG. 2). The neutralizing agent in the barrier coats thus improvesthe gastro-stability of the prototypes significantly.

Immediate Release Prototypes

Immediate release core (PD031-44), Opadry AMB-coated immediate releasecore (PD0231-27A) and an EC- barrier coated immediate release core(PD0231-38E) all showed an immediate release profile at pH 1.1.

Example 8 Canine PK Study

Four prototypes were used in the cross-over dog PK study, including animmediate release core (as the immediate release component in thecurrent invention, IR) (see Ex. 2), an Eudragit L 30 D-55 coated delayedrelease prototype (DR2) (see Ex. 6a), an Eudragit FS 30 D coated delayedrelease prototype (DR1-no acid) (see Ex. 6c) and an Eudragit FS 30 Dcoated delayed release prototype with malic acid as the neutralizingagent in the barrier coats (DR1-with acid) (see Ex. 6d). A total of 6dogs (3 males and 3 females) were given two oral capsules of one of theprototypes containing 1 g of sodium gamma-hydroxybutyrate per capsule.There was a minimum of a 2-day washout between each dose. Blood wascollected at the following time points: 0 (pre-dose), 0.5, 1, 2, 3, 4,5, 6, 7, 8, 10, 12, and 14 Hrs post dose (for a total of 312 samples).Plasma samples were analyzed using a verified LC/MS/MS method. Relativebioavailability was determined by comparing the AUC from the delayedrelease prototype group to the AUC of the immediate release prototypegroup.

The results show that the lower in the GI, the lower the bioavailability(BA); i.e., absorption is higher at upper GI. The immediate releasecomponent has the highest BA, so GHB may be absorbed better in its acidform. The BAs for the delayed release components with or without anneutralizer in the barrier coat do not very much so the neutralizerhelps the coating—in turn the gastro-stability—but does not affect theBA. See Table 3 and FIG. 7.

TABLE 3 Mean GHB Concentrations (ug/mL) Period 1 2 3 4 Time Point (Hr)DR1-w/ Acid DR1-No Acid IR DR2 0 0.00 0.00 0.00 0.00   0.5 0.00 0.00116.04 0.00 1 0.00 4.76 248.27 1.53 2 4.99 11.62 195.51 32.52 3 26.3131.88 117.56 100.99 4 35.14 38.26 47.21 100.57 5 29.18 34.77 8.74 54.996 21.09 27.83 0.00 23.42 7 11.25 9.13 0.00 7.52 8 8.67 2.53 0.00 0.3410  1.43 3.03 0.00 0.00 12  0.98 0.67 0.00 0.00 14  0.43 0.00 0.00 0.00Tmax (Hr) 4.2 5.2 1.2 3.7 Cmax (ug/mL) 38.77 58.44 249.5 112.7 AUClast134.3 162.6 601.0 318.4 Rel BA 22% 27% 100% 53%

1. A once-daily oral pharmaceutical dosage form, comprising: (a) aliquid immediate release component comprising a gamma-hydroxybutyricacid (GHB) salt, (b) a first delayed release component comprising theGHB salt, and (c) a second delayed release component comprising the GHBsalt, wherein the first delayed release component releases GHB in theduodenum and comprises a GHB containing core surrounded by a barriercoat, which in turn is surrounded by an enteric coating comprising a pHsensitive material that dissolves in the duodenum, and wherein thesecond delayed release component releases GHB in the colon and comprisesa GHB containing core surrounded by a barrier coat, which in turn issurrounded by a coating comprising a pH sensitive material thatdissolves in the colon.
 2. The oral dosage form of claim 1, wherein oneof the delayed release components releases GHB in the duodenum, and theother delayed release component releases GHB in the colon.
 3. The oraldosage form of claim 1, wherein the immediate release component ispresent in an amount that is equivalent to, higher than, or less thanthe amount of the one or more delayed release components.
 4. The oraldosage form of claim 3, wherein the delayed release component comprisesless GHB than the immediate release component.
 5. The oral dosage formof claim 4, wherein the immediate release component is combined with a0.7 equivalent dose of a duodenum-targeting delayed release component,and 0.2 equivalent dose of a colon-targeting delayed release component.6. A method for the treatment of a neurological disorder in a subject,comprising administering an effective amount of the oral dosage form ofclaim 1 to the subject.
 7. The method of claim 6, wherein the subject isa human.
 8. The method of claim 6 wherein said condition is selectedfrom Parkinson's disease, narcolepsy, cataplexy and sleep paralysis. 9.The oral dosage form of claim 1, wherein said delayed release componentcomprises particles containing GHB in a core, which core is immediatelysurrounded by a barrier coat to control the migration of GHB from thecore, which in turn is surrounded by an enteric release coat that allowsfor the release of GHB at a predetermined pH after ingestion.
 10. Theoral dosage form of claim 9, wherein said barrier coat contains aneutralizing agent or agents selected from the group consisting of malicacid, citric acid, tartaric acid, ascorbic acid, oleic acid, capricacid, caprylic acid, benzoic acid, a polyacid, and acidic ionic resins.11. The oral dosage form of claim 10, wherein the neutralizing agent(s)are used in amounts sufficient to neutralize any migratinggamma-hydroxybutyric acid salt.
 12. The oral dosage form of claim 11,wherein said neutralizing agent(s) are used in an amount of about 0.01%to about 10% mol of the amount of GHB in the core.
 13. The oral dosageform of claim 12, wherein the amount of the neutralizing agent is fromabout 1% to about 5% mol of the amount of the GHB in the core.
 14. Theoral dosage form of claim 9, wherein the barrier coat is composed ofmaterials selected from ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, cellulose acetate, celluloseacetate phthalate, and polyvinyl alcohol.
 15. The oral dosage form ofclaim 9, wherein the core is surrounded by more than one barrier coat.16. The oral dosage form of claim 15, wherein a first barrier coatcomprises polyvinyl alcohol, a second barrier coat comprisesethylcellulose, and a third barrier coat compriseshydroxypropylmethylcellulose.
 17. The oral dosage for of claim 9,wherein the enteric release coat is a pH sensitive material, whichallows for the release of GHB at a predetermined pH in thegastrointestinal tract.
 18. The oral dosage form of claim 17, whereinthe pH sensitive material comprises methacrylate-based coatingmaterials, cellulose-based coating materials, shellac-based coatingmaterials, polyvinyl acetate phthalate.
 19. The oral dosage form ofclaim 18, wherein the methacrylate-based coating materials are polymersof methacrylic acid and methacrylates.
 20. The oral dosage form of claim17, wherein the pH sensitive enteric release coat allows the release ofGHB in the upper gastrointestinal tract.
 21. The oral dosage form ofclaim 20, wherein the enteric release coat comprises amethacrylate-based coating material.
 22. The oral dosage form of claim18, wherein the enteric release coat further comprises acidic materialsthat counteract the alkaline effects of GHB.
 23. The oral dosage form ofclaim 18, wherein the cellulose-based coating materials are selectedfrom cellulose acetate phthalate, carboxymethyl ethylcellulose,cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate,and hydroxypropylmethylcellulose acetate succinate.
 24. The oral dosageform of claim 9, wherein the core further comprises one or moreexcipients selected from binders, lubricants, anti-adherents, glidantsand neutralizing agents.
 25. The oral dosage form of claim 24, whereinthe excipients are selected from talc, sodium lauryl fumarate, fumedsilicon dioxide, magnesium stearate, stearic acid and combinationsthereof.
 26. The oral dosage form of claim 25, wherein the excipientsare selected from one or both of talc and magnesium stearate.
 27. Theoral dosage form of claim 26, wherein the talc is present in an amountof about 1% to about 25% by weight of the core.
 28. The oral dosage formof claim 27, wherein the amount of talc present is between about 5% andabout 15% by weight of the core.
 29. The oral dosage form of claim 26,wherein the magnesium stearate is present in an amount of about 0.1% to10% by weight of the core.
 30. The oral dosage form of claim 29, whereinthe amount of magnesium stearate is from about 0.1% to about 5% byweight of the core.